Just like a ship without a captain, the malfunction of the RNA-binding protein hnRNP A1 can have dire consequences for the energy production in Alzheimer’s disease models. Using clever experiments with mouse hippocampal neurons, scientists discovered that hnRNP A1 plays a vital role in regulating glycolysis, which is the process by which cells convert glucose into energy. By inhibiting the binding of hnRNP A1 to HK1 RNA, the key proteins involved in glycolysis are disrupted, leading to dysfunction in the energy-generating pathway. Furthermore, they found that overexpression of hnRNP A1 protected against toxic effects of Aβ25–35, a protein associated with Alzheimer’s, by activating the hnRNP A1/HK1/pyruvate pathway. Additionally, they observed a bidirectional regulation between hnRNP A1 and amyloid precursor protein (APP) RNA, with inhibition of HNRNP-A1 contributing to increased Aβ expression. The research also revealed that hnRNP A1 decreases with age and even more so in AD mice, suggesting its involvement in the development of Alzheimer’s. To learn more about this fascinating study on the relationship between RNA binding and energy failure in Alzheimer’s disease, check out the link provided!

ObjectiveTo investigate the mechanism of RNA-binding protein hnRNP A1 in mouse hippocampal neurons (HT22) on glycolysis.MethodsRIP and CLIP-qPCR were performed by HT22 in vitro to observe the mechanism of HNRNP-A1 regulating the expression of key proteins in glycolysis. The RNA binding domain of hnRNP A1 protein in HT22 was inhibited by VPC-80051, and the effect of hnRNP A1 on glycolysis of HT22 was observed. Lentivirus overexpression of HNRNP-A1 was used to observe the effect of overexpression of HNRNP-A1 on glycolysis of Aβ25–35-injured HT22. The expression of hnRNP A1 in brain tissues of wild-type mice and triple-transgenic (APP/PS1/Tau) AD mice at different ages was studied by Western blot assay.ResultsThe results of RIP experiment showed that hnRNP A1 and HK1 mRNA were significantly bound. The results of CLIP-qPCR showed that hnRNP A1 directly bound to the 2605-2821 region of HK1 mRNA. hnRNP A1 inhibitor can down-regulate the expression of HK1 mRNA and HK1 protein in HT22 cells. Overexpression of hnRNP A1 can significantly reduce the toxic effect of Aβ25–35 on neurons via the hnRNP A1/HK1/ pyruvate pathway. In addition, inhibition of HNRNP-A1 binding to amyloid precursor protein (APP) RNA was found to increase Aβ expression, while Aβ25–35 also down-regulated HNRNP-A1 expression by enhancing phosphorylation of p38 MAPK in HT22. They interact to form bidirectional regulation, further down-regulating the expression of hnRNP A1, and ultimately aggravating glycolytic dysfunction. Protein immunoblotting showed that hnRNP A1 decreased with age in mouse brain tissue, and the decrease was greater in AD mice, suggesting that the decrease of hnRNP A1 may be a predisposed factor in the pathogenesis of AD.

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